MYRF rs174535 — A Gateway Variant for Omega-3 Status in the FADS Region
Chromosome 11's 11q12 region is home to one of the most influential loci
for polyunsaturated fatty acid (PUFA) metabolism in the human genome — the
FADS gene cluster encoding the delta-5 and delta-6 desaturase enzymes
that convert dietary fatty acid precursors into the long-chain omega-3 and
omega-6 fatty acids your cells actually use. rs174535 sits within the
MYRF gene | Myelin Regulatory Factor, a transcription factor encoded at
chr11:61,752,636–61,788,518 whose primary known function is promoting
oligodendrocyte differentiation and central nervous system myelination,
approximately 55 kilobases downstream of the FADS1 gene. Despite MYRF's
primary role in myelin biology, carriers of the rs174535 C allele
consistently show lower circulating omega-3 PUFA and DHA concentrations —
a finding that has reached genome-wide significance in independent cohorts.
The Mechanism
rs174535 creates a missense substitution (Ser1051Arg) in MYRF isoform 2.
Whether this amino acid change directly alters fatty acid metabolism is
uncertain — MYRF is not known to participate in lipid desaturation
pathways. The more plausible explanation is
linkage disequilibrium (LD) | A statistical correlation between nearby
genetic variants meaning they are co-inherited more often than expected
by chance; variants in the same haplotype block act as proxies for each
other in association studies
with functional variants in the FADS1 and FADS2 genes immediately
upstream. The entire 11q12.2 region — spanning FADS1, FADS2, FADS3,
TMEM258, FEN1, and MYRF — shows strong patterns of LD, meaning rs174535
may function as a tag SNP capturing the effect of nearby FADS variants
on the same haplotype. A secondary possibility, not yet ruled out, is
that Ser1051Arg alters MYRF's transcriptional targets in a way that
indirectly feeds back on lipid homeostasis.
The Evidence
The primary evidence comes from a genome-wide association study of serum
omega-3 and omega-6 PUFA concentrations | Coltell et al., Nutrients 2020,
PMID 31991592 — multicenter cross-sectional GWAS in Mediterranean subjects
with metabolic syndrome.
In an additive model, each additional C allele at rs174535 was associated
with a decrease of 0.339 percentage points in serum omega-3 PUFA
(p = 1.49 × 10⁻¹²) and a decrease of 0.111 percentage points in DHA
specifically (p = 3.89 × 10⁻¹⁰) — both surpassing the genome-wide
significance threshold. The variant was independently replicated in the
UK Biobank (N = 188,700), where rs174535 reached p = 1.6 × 10⁻¹² for
omega-3 fatty acid levels.
The broader FADS locus context further supports the interpretation.
A landmark GWAS of plasma phospholipid PUFAs in 1,075 InCHIANTI
participants | Tanaka et al. 2009, PLoS Genetics, PMID 19148276
established that variants in this chromosomal region account for up to
18.6% of additive variance in arachidonic acid levels and significantly
associate with EPA levels. The CHARGE Consortium meta-analysis
(n=8,866) | Lemaitre et al. 2011, PLoS Genetics, PMID 21829377
further confirmed that the FADS1/FADS2 haplotype block drives lower
circulating EPA and DPA in Europeans.
Practical Actions
For CC homozygotes: lower circulating omega-3 and DHA levels indicate
that endogenous PUFA synthesis (whether from MYRF LD effects on FADS
activity or from independent mechanisms in the haplotype block) is
operating below average capacity. Supplementing with preformed EPA and
DHA from marine or algae-based sources bypasses any conversion
impairment and directly raises circulating levels. Targeting 2–3 g of
combined EPA+DHA daily is appropriate for CC homozygotes.
For CT heterozygotes: one C allele produces a statistically intermediate
reduction in omega-3 levels. A daily 1–2 g EPA+DHA supplement from
marine fish or algae covers the gap without overcompensating.
Monitoring the omega-3 index (erythrocyte EPA+DHA as % of total fatty
acids) provides a direct readout of whether supplementation is achieving
the target range (8–12%). This is especially useful for CC carriers to
confirm adequacy.
Interactions
rs174535 lies within the same haplotype block as FADS1 rs174537 and
FADS1 rs174547 — the two most extensively studied PUFA-associated variants
in this region. In individuals who also carry the risk alleles at rs174537
(G allele) or rs174547 (C allele), the combined haplotype may compound
the effect on omega-3/DHA levels. Future compound action analyses
should evaluate the combined effect of rs174535 CC × rs174537 GG, as
both converge on reduced EPA and DHA availability through potentially
complementary mechanisms.
Alla genotyper
Common genotype — typical circulating omega-3 and DHA levels
You carry two copies of the T allele at rs174535, the GRCh38 reference allele and the more common variant globally (approximately 43% of people are TT homozygotes). This genotype is associated with average or above-average circulating omega-3 PUFA and DHA concentrations at this locus — no C-allele-driven reduction in PUFA levels is present. Your omega-3 and DHA status will still depend substantially on how much preformed EPA and DHA you consume through diet and supplements, but this variant does not impose an additional genetic disadvantage.
One C allele — moderately reduced circulating omega-3 and DHA
You carry one copy of the C allele at rs174535. In GWAS studies, each additional C allele is associated with a decrease in circulating omega-3 PUFA and DHA concentrations. As a heterozygote, you have an intermediate effect — lower average omega-3 levels than TT carriers but not as low as CC homozygotes. Approximately 45% of people carry this CT genotype. The practical implication is that your circulating omega-3 status may trend below average if your dietary intake of preformed EPA/DHA is not adequate. A moderate daily EPA+DHA supplement brings levels into the optimal range.
Two C alleles — meaningfully lower circulating omega-3 and DHA levels
You carry two copies of the C allele at rs174535, the genotype most strongly associated with reduced circulating omega-3 PUFA and DHA concentrations in GWAS data. Approximately 12% of the global population carries this CC genotype; it is more common in East Asian and Latin American ancestry groups (up to ~40% CC frequency) and less common in African and South Asian populations (~3–4% CC). Each C allele is associated with a reduction of 0.339 percentage points in serum omega-3 PUFA. Two alleles together produce the maximum genetic reduction at this locus — a clinically meaningful difference particularly when dietary EPA/DHA intake is low. Low omega-3 levels are associated with increased cardiovascular risk, impaired resolution of inflammation, and suboptimal DHA supply to the brain and retina. Because this variant likely tags the FADS haplotype block rather than acting through MYRF directly, the practical consequence mirrors what is seen for low-FADS-activity genotypes: inadequate endogenous conversion of dietary fatty acid precursors into long-chain omega-3 products, combined with a constitutively lower circulating omega-3 baseline.